Proposal Abstract Fertility in women can be compromised by various environmental factors, including the medications they take, which may interfere with embryo development in the reproductive tract. Human epidemiological studies have been helpful to identify drugs that cause birth defects or fetal death. However, environmental insults on preimplantation stages, i.e., the first week of embryo development from fertilization to implantation, are nearly impossible to detect by epidemiology, because women become aware of being pregnant only after embryo implantation. If embryos are damaged by a toxic agent before implantation, women cannot even recognize they produced an embryo. To identify environmental insults that compromise embryos before implantation, we need to understand the molecular mechanisms behind preimplantation development, so that chemical agents that interfere with those mechanisms can be suspected as preimplantation toxicants. The proposed project investigates the role of the mevalonate pathway, the primary target of major cholesterol- lowering medications, in the first cell fate decision in preimplantation embryos. The project specifically focuses on how one of the end products of the mevalonate pathway, geranylgeranyl pyrophosphate, controls the activity of RHO small GTPase and HIPPO signaling to promote differentiation of the trophectoderm, i.e., the extraembryonic lineage responsible for implantation and placenta formation. The proposed studies should yield valuable information on how the crucial aspects of preimplantation development are regulated by the mevalonate pathway, and lay foundation for future research to determine the reproductive impact of cholesterol-lowering medications.